Non-Motor Symptoms of Parkinson's Disease: The Neurobiology of Early Psychiatric and Cognitive Dysfunction

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that has been recognized for over 200 years by its clinically dominant motor system impairment. There are prominent non-motor symptoms as well, and among these, psychiatric symptoms of depression and anxiety and cognitive impairment are common and can appear earlier than motor symptoms. Although the neurobiology underlying these particular PD-associated non-motor symptoms is not completely understood, the identification of PARK genes that contribute to hereditary and sporadic PD has enabled genetic models in animals that, in turn, have fostered ever deepening analyses of cells, synapses, circuits, and behaviors relevant to non-motor psychiatric and cognitive symptoms of human PD. Moreover, while it has long been recognized that inflammation is a prominent component of PD, recent studies demonstrate that brain-immune signaling crosstalk has significant modulatory effects on brain cell and synaptic function in the context of psychiatric symptoms. This review provides a focused update on such progress in understanding the neurobiology of PD-related non-motor psychiatric and cognitive symptoms.

Keywords: LRRK2; Parkinson’s disease; SNCA; Vps35; neurodegeneration; non-motor symptoms; social defeat stress; synaptic plasticity.

Figure 1.

PARK genes are expressed in brain during development and in adulthood. (A) Photomicrographs of sagittal sections through adult mouse brains following in situ hybridization to show regional distribution patterns of LRRK2, SNCA (αSyn), and VPS35 expression. (B) Expression levels of αSyn, VPS35, and LRRK2 rise during early postnatal development contemporaneously with synaptogenesis in striatum and elsewhere. Photomicrographs are taken from the Allen Mouse Brain Atlas (Lein and others 2007) and these and figure B reprinted with permission from Benson and Huntley (2019).

Figure 2.

Distinct behavioral and neural adaptations to acute (1d) social defeat stress (1d-SDS) in wild-type (WT) and Lrrk2^G2019S mice. (A) Schematic of the 1d-SDS paradigm followed by the social interaction (SI) test. In this paradigm, a WT or mutant C57Bl6 mouse is put into the home cage of a larger, CD1 retired male breeder. The larger CD1 aggressor physically subordinates the smaller C57Bl6 intruder for 5 minutes, then the two mice are separated for 15 minutes by a perforated divider, preventing further physical contact but maintaining the exchange of sensory cues. This process is repeated 2 more times on the same day, then the defeated mouse is returned to its home cage overnight. The next day, the mouse is subjected to an SI test, where the defeated mouse is allowed to explore an arena in the absence and subsequent presence of a novel social target constrained by a wire cage at one end of the arena. Video tracking monitors the amount of time the defeated mouse spends exploring the interaction zone with and without the social target present. (B) Heat maps showing movement of WT and Lrrk2^G2019S mice during the SI test following 1d-SDS. Blue indicates path traveled; warmer colors indicate increased time. (C, D) Bar graphs/scatter plots showing time spent in the interaction zone during the SI test in the absence of a social target (C, P = 0.5478) and when the social target is present (D, P = 0.0117; WT, n = 13 mice; G2019S, n = 12 mice). Defeated mutant mice are significantly more socially avoidant in comparison with defeated WT mice. (E) Lrrk2^G2019S mice show significantly greater sucrose consumption—a hedonic response—after 1d-SDS compared with 1d-SDS WT mice (P = 0.0432, WT, n = 7 mice; G2019S, n = 8 mice). (F) The intrinsic excitability of striatal projection neurons (SPNs) in the nucleus accumbens (NAc) is significantly elevated by 1d-SDS in WT mice—presumably an adaptive response to stress—but 1d-SDS does not alter intrinsic excitability of SPNs in Lrrk2^G2019S mice. The input/output plot shows the number of action-potentials (spike number) elicited in response to depolarizing current steps applied to SPNs in the NAc. For each current step, defeated WT mice elicited more spikes in comparison with defeated G2019S mice or no-stress WT and G2019S control groups (at 140 pA: P = 0.0189; at 160 pA: P = 0.0115; at 180 pA: P = 0.0064; at 200 pA: P = 0.0095). Current step × genotype: F(42, 770) = 5.766, P < 0.001; main effect current step: F(2.307, 126.9) = 78.06, P < 0.001; main effect genotype: F(3, 55) = 8.658, P < 0.0001. (G) Representative traces of action potentials generated by current injection (180-pA step) into NAc SPNs taken from mice from each behavioral condition shown. All data are reproduced with permission from Guevara and others (2020).

Figure 3.

Lrrk2^G2019S mice are behaviorally resilient to effects of chronic 10-day social defeat stress (10d-SDS). (A) Schematic of the 10d-SDS paradigm followed by the social interaction (SI) test. For details, see legend to Figure 2 (B) Heat maps showing movement of wild-type (WT) and Lrrk2^G2019S (GSKI) mice during the SI test following 10d-SDS. Blue indicates path traveled; warmer colors indicate increased time. Note that following 10d-SDS, the WT mouse shown avoids the interaction zone when the novel social target is present, while in contrast, the GSKI mouse spends significant time in the interaction zone when the novel social target is present, despite 10 days of defeat experience. (C) Bar graphs/scatter plots depicting social interaction as a ratio (SI ratio), defined as the time a mouse spends in the interaction zone with a social target present divided by the time spent in the interaction zone when the social target is absent. By convention, ratios <1 are termed “susceptible” to SDS, while ratios >1 are termed “resilient” to SDS. In WT mice, 10d-SDS produces the expected frequency of about half that are susceptible (sus) and the other half that are resilient (res), compared with unstressed WT controls (con). In contrast, virtually all GSKI mice are resilient following 10d-SDS, a significant departure from WT mice (P = 0.00001, F = 6.607, one-way analysis of variance with Bonferroni post hoc tests, n = 8 control mice per genotype, 6 WT susceptible, 8 WT resilient; n = 1 GSKI susceptible, and 15 GSKI resilient). In the absence of social defeat, there are no differences between genotypes in the social interaction behavior of the unstressed control groups. (D) A significantly greater fraction of GSKI mice are resilient to chronic SDS (P = 0.0309, Fisher’s exact test, n = 14 WT and 16 GSKI). All data are reprinted with permission from Matikainen-Ankney and others (2018).

Figure 4.

Nuclear factor κB (NF-κB)-mediated transcription may represent molecular convergence of Parkinson’s disease (PD), behavioral stress, and aberrant immune signaling. (Top) The NF-κB transcriptional pathway can be activated by several behavioral or molecular signals, including stress and extracellular accumulations of αSyn fibrils. (Middle) NF-κB-mediated transcription drives synthesis and secretion of a number of inflammatory cytokines in CNS microglia and in cells of the peripheral immune system. (Bottom) Inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-8), interferon-γ, tumor necrosis factor-α [TNF-α]) gain access to the brain and can modify circuit function and synaptic plasticity, participating in molecular changes that lead to psychiatric (depression and anxiety)-like behaviors or, more speculatively, cognitive deficits in mouse models. See text for further details.

Figure 5.

Several PARK proteins converge functionally on molecular signaling cascades regulating vesicle sorting and trafficking on both pre- and postsynaptic sides of synapses in striatum and elsewhere. (Top) Both D₁R (direct)- and D₂R (indirect)-spiny striatal projection neurons (SPNs) receive convergent excitatory synaptic input from several sources, as well as dopaminergic input from the substantia nigra or ventral tegmental area (VTA). Through these varied inputs, SPNs mediate a variety of cognitive and motor functions. BLA, basolateral amygdala; mPFC, medial prefrontal cortex. (Middle) A representative example of an excitatory corticostriatal synapse demonstrating the molecular signaling cascades in which various PARK proteins participate. On the presynapse side, LRRK2, α-synuclein (αSyn), Synaptojanin (Synj1), Auxilin, PINK1, and Parkin regulate different aspects of neurotransmitter-containing vesicle exocytocis and endocytocis. On the postsynaptic side, LRRK2, Parkin, and Vps35 regulate vesicle sorting and trafficking, including that of AMPARs important for synaptic transmission and plasticity. PD-associated mutations in these proteins can impair AMPAR trafficking. See text for further details. (Bottom) PD-associated mutations in these PARK proteins in mice affect synaptic neurotransmission and impair plasticity such as LTP at striatal synapses, which in turn can lead to depression- and anxiety-like behaviors and cognitive deficits of the kind that may be relevant to NMS in patients with PD.

Figure 6.

AMPA-type glutamate receptors (AMPARs) at nucleus accumbens (NAc) synapses lack calcium-permeable (CP) subunits in Lrrk2^G2019S mice. (A) AMPAR-mediated excitatory postsynaptic currents (EPSCs) (traces, left) were evoked at NAc synapses in acute striatal slices taken from adult wild type (WT) or Lrrk2^G2019S knockin (GSKI) mice at baseline (solid line) and following bath-application of NASPM (1-naphthylacetyl spermine), an antagonist of CP-AMPAR subunits (dotted line). Mutant synapses were insensitive to NASPM, illustrating a lack of CP-AMPAR subunits, a significantly different response compared with WT synapses (right graph). P = 0.0028, F = 2.599, n = 7 cell/4 WT mice; n = 7 cells/4 GSKI mice. Student’s t test. (B) Western blots showing protein levels of GluA1, GluA2, and actin in total (T) and synaptic (S) fractions taken from adult WT or Lrrk2^G20l9S (GS) mice. (C) There were no significant differences between genotypes in GluA1 or GluA2 levels in total or synaptic (syn) fractions. Within both genotypes, GluA1 and GluA2 were significantly enriched in the synaptic fraction compared with total fractions as expected (analysis of variance, P = 0.0001; n = 4 per genotype). (D) Confocal microscope single-optical images (left) and after threshold was applied (right) showing immunoreactive (IR) GluA2 in the NAc. (E) Quantitative morphometric analysis of GluA2-labeled puncta in NAc showed no significant differences in puncta density or size between WT and GSKI mice, P = 0.2955 for area, and P = 0.7226 for density. All data reproduced with permission from Matikainen-Ankney and others (2018).

Figure 7.

Long-term potentiation (LTP) is disrupted by PD–associated mutations in LRRK2 or Vps35. (A) In dorsomedial striatum of wild type (WT) mice, an LTP-induction protocol in which presynaptic stimulation of corticostriatal fibers is paired with brief postsynaptic depolarization (to 0 mV, bar) of striatal projection neurons (SPNs) results in robust LTP of corticostriatal synapses (gray circles). Such LTP is NMDAR-dependent, shown by the abrogation of potentiation in the presence of the NMDAR antagonist APV (gray/white split circles). In contrast, the same LTP-induction protocol applied to acute striatal slices from GSKI (Lrrk2^G2019S knockin) mice produces a long-term depression (LTD)–like plasticity of corticostriatal synapses (blue circles). In these experiments, the subtype identity of SPNs was unknown. (B) When parsed by SPN subtype, both D₁R-SPNs (closed circles) and D₂R-SPNs (open circles) in the GSKI mice failed to exhibit LTP, but only the D₂R-subtype responded to the LTP-induction protocol with aberrant LTD. (C) Average excitatory postsynaptic current (EPSC) traces before (gray, baseline) and after (black) applying the LTP-induction protocol to D₁R- or D₂R-SPNs in GSKI mice. Data shown in A to C reprinted from Matikainen-Ankney and others (2018). (D) In acute hippocampal slices, shRNA-mediated knockdown of Vps35 (green circles) blocked NMDAR-dependent LTP of Schaffer collateral-area CA1 synapses compared to uninfected controls (black circles). LTP was rescued by co-transfecting hippocampal neurons with a shRNA-resistant form of Vps35 (red circles). (E) In hippocampus, LTP rendered deficient by shRNA-knockdown of Vps35 is rescued by co-transfection with Vps35^L625P, an Alzheimer’s disease associated mutation, but not by co-transfection with Vps35^D620N, a PD-associated mutation. Data in D and E reprinted with permission from Temkin and others (2017).